The acyclic hydrazides of the invention are antagonists and/or inverse agonists of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. The compounds of the present invention are useful as centrally acting drugs in the...http://www.google.com/patents/US20080076805?utm_source=gb-gplus-sharePatent US20080076805 - Antagonists and/or inverse agonists of CB1; N'-[1-(3-chlorophenyl)-2-(4-chlorophenyl)ethyl]-N'-methyl-N-(2-methyl-2-[5-(trifluoromethylpyridin-2-yl)oxy]propanoyl)hydrazide for example; obesity, psychological disorders, analgesics, drug abuse, constipation, asthma, cirrhosis

The acyclic hydrazides of the invention are antagonists and/or inverse agonists of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. The compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders (including smoking cessation), the treatment of obesity or eating disorders, as well as the treatment of asthma, constipation, chronic intestinal pseudo-obstruction, and cirrhosis of the liver.

Images(35)

Claims(18)

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein;

R1 is selected from:

(1) hydrogen,

(2) C1-4alkyl,

(3) C3-6cycloalkyl,

(4) C2-4alkenyl, and

(5) C2-4alkynyl;

R2 is selected from:

(1) C1-10alkyl,

(2) C2-10alkenyl,

(3) C2-10alkynyl,

(4) C3-10cycloalkyl,

(5) C3-10cycloalkyl C1-4alkyl,

(6) cycloheteroalkyl,

(7) cycloheteroalkyl C14alkyl

(8) aryl,

(9) aryl C1-10alkyl,

(10) aryl C2-8alkenyl,

(11) diaryl C1-4alkyl,

(12) heteroaryl,

(13) heteroaryl C1-10alkyl,

(14) NRcRd,

wherein each alkyl, alkenyl, and alkynyl is straight or branched chain and unsubstituted or substituted with one to four substituents independently selected from Ra and each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to four substituents independently selected from Rb;

Ar1 and Ar2 are independently selected from:

(1) aryl, and

(2) heteroaryl,

wherein aryl and heteroaryl are unsubstituted or substituted with one to four substituents independently selected from Rb;

each Ra is independently selected from:

(1) —ORd,

(2) —NRcS(O)mRd,

(3) halogen,

(4) —SRd,

(5) —S(O)mRd,

(6) —S(O)mNRcRd,

(7) —NRcRd,

(8) —C(O)Rd,

(9) —CO2Rd,

(10) —CN,

(11) —C(O)NRcRd,

(12) —NRcC(O)Rd,

(13) —NRcC(O)ORd,

(14) —NRcC(O)NRcRd,

(15) —CF3, and

(16) —OCF3;

each Rb is independently selected from:

(1) Ra,

(2) C1-10alkyl,

(3) oxo,

(4) aryl,

(5) arylC1-4alkyl,

(6) heteroaryl, and

(7) heteroarylC1-4alkyl;

each Rc and Rd is independently selected from:

(1) hydrogen,

(2) C1-10alkyl,

(3) C2-10alkenyl,

(4) cycloalkyl,

(5) cycloalkyl-C1-10alkyl,

(6) cycloheteroalkyl,

(7) cycloheteroalkyl-C1-10alkyl,

(8) aryl,

(9) heteroaryl,

(10) pyridyl,

(11) pyrimidyl,

(12) aryl-C1-10alkyl, and

(13) heteroaryl-C1-10alkyl, or

Rc and Rd together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—Rg,

each Rc and Rd may be unsubstituted or substituted with one to three substituents selected from Rh;

each Rg is independently selected from:

(1) hydrogen,

(2) C1-4alkyl,

(3) —C(O)C1-4alkyl,

(4) —C(O)ORd,

(5) —C(O)NRcRd,

(6) —S(O)mRd, and

(7) —S(O)mNRcRd;

each Rh is independently selected from:

(1) halogen,

(2) C1-10alkyl,

(3) —O—C1-4alkyl,

(4) —S—C1-4alkyl,

(5) —S(O)m—C1-4alkyl,

(6) —CN,

(7) —NO2,

(8) —CF3,

(9) —CHF2 and

(10) —OCF3; and

m is selected from 1 and 2.

2. The compound according to claim 1, wherein:

Ar1 is selected from: phenyl, and pyridyl, wherein phenyl and pyridyl are unsubstituted or substituted with one to three Rb substituents; and

Ar2 is selected from: phenyl, and pyridyl, wherein phenyl and pyridyl are unsubstituted or substituted with one to three Rb substituents,

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, wherein:

Ar1 is para-chlorophenyl and Ar2 is selected from: m-chlorophenyl, m-bromophenyl, and m-cyanophenyl,

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, wherein:

R1 is selected from:

(1) hydrogen,

(2) methyl,

(3) ethyl,

(4) propyl, and

(5) allyl,

or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, wherein:

R2 is selected from:

(1) C1-8 alkyl,

(2) C3-6 cycloalkyl,

(3) cycloheteroalkyl,

(4) phenyl,

(5) phenyl C1-3 alkyl,

(6) pyridyl,

(7) pyrimidyl,

(8) pyridyl C1-3 alkyl, and

(9) pyrimidyl C1-3 alkyl,

wherein each alkyl moiety is straight or branched chain and unsubstituted or substituted with one, two or three substituents independently selected from Ra, and each cycloalkyl, cycloheteroalkyl, phenyl, and heteroaryl moiety is unsubstituted or substituted with one, two or three substituents independently selected from Rb;

each Rb is independently selected from:

(1) —ORd,

(2) halogen,

(3) —CN,

(4) —CF3,

(5) —OCF3,

(6) cycloheteroalkyl;

(7) C1-4alkyl,

(8) oxo,

(9) phenyl,

(10) benzyl, and

(11) heteroaryl;

each Rd is independently selected from:

(1) hydrogen,

(2) C1-5alkyl,

(3) —CH2CH═CH2,

(4) cyclohexyl,

(5) cyclopentyl,

(6) cyclopropyl,

(7) cyclobutylmethyl,

(8) cyclopentylmethyl,

(9) cyclohexylmethyl,

(10) pyrrolidinyl,

(11) phenyl,

(12) thiazolyl,

(13) pyridyl,

(14) pyrimidyl,

(15) benzothiazolyl,

(16) benzoxazolyl,

(17) triazolyl,

(18) benzyl, and

(19) pyridyl-methyl-,

wherein each Rd may be unsubstituted or substituted with one to three substituents selected from Rh;

each Rh is independently selected from:

(1) halogen,

(2) methyl,

(3) methoxy,

(4) —S(O)m—C1-4alkyl,

(5) —CN,

(6) —CF3,

(7) —CHF2, and

(8) —OCF3;

or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, wherein:

R2 is selected from:

each Rd is independently selected from:

(1) hydrogen,

(2) phenyl,

(3) pyridyl, and

(4) pyrimidyl,

wherein phenyl, pyridyl and pyrimidyl are unsubstituted or substituted with one or two Rh substituents; and

each Rg is independently selected from:

(1) hydrogen,

(2) C1-4alkyl;

or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, selected from the group consisting of:

15. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

16. The composition according to claim 15 additionally comprising an HMG-CoA reductase inhibitor.

17. The composition according to claim 15 additional comprising 7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine, or a pharmaceutically acceptable salt thereof.

18. A method of treating a disease mediated by the Cannabinoid-1 receptor in a subject in need thereof comprising administering a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

20. A method of treating obesity in a subject in need thereof comprising administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

21. A method of reducing body weight in a subject in need thereof comprising administration of a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

22. A method of maintaining the weight of an obese subject comprising administration of an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

23. A method of reducing the body weight of a subject at risk for obesity comprising administration of an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

24. A method of treating obesity in a subject in need thereof comprising administration of a therapeutically effective amount of a compound according to claim 7, or a pharmaceutically acceptable salt thereof.

Description

BACKGROUND OF THE INVENTION

Marijuana (Cannabis sativa L.) and its derivatives have been used for centuries for medicinal and recreational purposes. A major active ingredient in marijuana and hashish has been determined to be Δ9-tetrahydrocannabinol (Δ9-THC). Detailed research has revealed that the biological action of Δ9-THC and other members of the cannabinoid family occurs through two G-protein coupled receptors termed CB1 and CB2. The CB1 receptor is primarily found in the central and peripheral nervous systems and to a lesser extent in several peripheral organs. The CB2 receptor is found primarily in lymphoid tissues and cells. Three endogenous ligands for the cannabinoid receptors derived from arachidonic acid have been identified (anandamide, 2-arachidonoyl glycerol, and 2-arachidonyl glycerol ether). Each is an agonist with activities similar to Δ9-THC, including sedation, hypothermia, intestinal immobility, antinociception, analgesia, catalepsy, anti-emesis, and appetite stimulation.

There are at least two CB1 modulators characterized as inverse agonists or antagonists, N-(1-piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR141716A), and 3-(4-chlorophenyl-N′-(4-chlorophenyl)sulfonyl-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (SLV-319), in clinical trials for treatment of eating disorders and/or smoking cessation at this time. There still remains a need for potent low molecular weight CB1 modulators that have pharmacokinetic and pharmacodynamic properties suitable for use as human pharmaceuticals.

The compounds of the present invention are modulators of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the Cannabinoid-1 (CB1) receptor. Compounds of the present invention are antagonists or inverse agonists of the CB1, receptor. The invention is concerned with the use of these compounds to modulate the Cannabinoid-1 (CB1) receptor. As such, compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, such as for example, those relating to opiates, alcohol, marijuana, and nicotine. The compounds are also useful for the treatment of eating disorders by inhibiting excessive food intake and the resulting obesity and complications associated therewith, including left ventricular hypertrophy. The compounds are also useful for the treatment of constipation and chronic intestinal pseudo-obstruction, as well as for the treatment of asthma, and cirrhosis of the liver.

SUMMARY OF THE INVENTION

The present invention is concerned with substituted aralkyl amine derivatives of general formula

stereoisomers and pharmaceutically acceptable salts thereof which are modulators, and in particular, antagonists and/or inverse agonists, of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention or suppression of diseases mediated by the Cannabinoid-1 (CB1) receptor. The invention is concerned with the use of these novel compounds to selectively antagonize the Cannabinoid-1 (CB1) receptor. As such, compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, such as for example, those relating to opiates, alcohol, marijuana, and nicotine, including smoking cessation. The compounds are also useful for the treatment of obesity or eating disorders associated with excessive food intake and complications associated therewith, including left ventricular hypertrophy. The compounds are also useful for the treatment of constipation and chronic intestinal pseudo-obstruction. The compounds are also useful for the treatment of cirrhosis of the liver. The compounds are also useful for the treatment of asthma.

The present invention is also concerned with treatment of these conditions, and the use of compounds of the present invention for manufacture of a medicament useful in treating these conditions. The present invention is also concerned with treatment of these conditions through a combination of compounds of formula I and other currently available pharmaceuticals.

The invention is also concerned with pharmaceutical formulations comprising one of the compounds as an active ingredient.

The invention is further concerned with processes for preparing the compounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The compounds used in the methods of the present invention are represented by structural formula I:

wherein each alkyl, alkenyl, and alkynyl is straight or branched chain and unsubstituted or substituted with one to four substituents independently selected from Ra and each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to four substituents independently selected from Rb;

Ar1 and Ar2 are independently selected from:

(1) aryl, and

(2) heteroaryl,

wherein aryl and heteroaryl are unsubstituted or substituted with one to four substituents independently selected from Rb;

each Ra is independently selected from:

(1) —ORd,

(2) —NRcS(O)mRd,

(3) halogen,

(4) —SRd,

(5) —S(O)mRd,

(6) —S(O)mNRcRd,

(7) —NRcRd,

(8) —C(O)Rd,

(9) —CO2Rd,

(10) —CN,

(11) —C(O)NRcRd,

(12) —NRcC(O)Rd,

(13) —NRcC(O)ORd,

(14) —NRcC(O)NRcRd,

(15) —CF3, and

(16) —OCF3;

each Rb is independently selected from:

(1) Ra,

(2) C1-10alkyl,

(3) oxo,

(4) aryl,

(5) arylC1-4alkyl,

(6) heteroaryl, and

(7) heteroarylC1-4alkyl,

each Rc and Rd is independently selected from:

(1) hydrogen,

(2) C1-10alkyl,

(3) C2-10 alkenyl,

(4) cycloalkyl,

(5) cycloalkyl-C1-10alkyl;

(6) cycloheteroalkyl,

(7) cycloheteroalkyl-C1-10alkyl,

(8) aryl,

(9) heteroaryl,

(10) pyridyl,

(11) pyrimidyl,

(12) aryl-C1-10alkyl, and

(13) heteroaryl-C1-10alkyl, or

Rc and Rd together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—Rg, each Rc and Rd may be unsubstituted or substituted with one to three substituents selected from Rh;

each Rg is independently selected from:

(1) hydrogen,

(2) C1-4alkyl, and

(3) —C(O)C1-14alkyl,

(4) —C(O)ORd,

(5) —C(O)NRcRd,

(6) —S(O)mRd, and

(7) —S(O)mNRcRd;

each Rh is independently selected from:

(1) halogen,

(2) C1-10alkyl,

(3) —O—C1-4alkyl,

(4) —S—C1-4alkyl,

(5) —S(O)m—C1-4alkyl,

(6) —CN,

(7) —NO2,

(8) —CF3,

(9) —CHF2 and

(10) —OCF3; and

m is selected from 1 and 2.

In one embodiment of the present invention, R1 is selected from: hydrogen, C1-4alkyl, C2-4alkenyl, and C2-4alkynyl.

In one class of this embodiment, R1 is selected from: hydrogen, C1-4alkyl and C2-4alkenyl.

In a subclass of this class, R1 is selected from: hydrogen, methyl, ethyl, propyl, and allyl.

each alkyl, alkenyl, and alkynyl is straight or branched chain and unsubstituted or substituted with one, two, three, or four substituents independently selected from Ra, and each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one, two, three or four substituents independently selected from Rb.

each alkyl and alkenyl is straight or branched chain and unsubstituted or substituted with one, two or three substituents independently selected from Ra, and each cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is unsubstituted or substituted with one, two or three substituents independently selected from Rb.

each alkyl moiety is straight or branched chain and unsubstituted or substituted with one, two or three substituents independently selected from Ra, and each cycloalkyl, cycloheteroalkyl, phenyl, and heteroaryl moiety is unsubstituted or substituted with one, two or three substituents independently selected from Rb.

each alkyl moiety is unsubstituted or substituted with one or two Ra substituents, and each cycloalkyl, cycloheteroalkyl, or phenyl moiety is unsubstituted or substituted with one or two Rb substituents.

In yet another subclass, R2 is selected from:

In yet another embodiment of the present invention, Ar1 is selected from:

aryl and heteroaryl, wherein aryl and heteroaryl are unsubstituted or substituted with one, two, three, or four substituents independently selected from Rb.

In a class of this embodiment, Ar1 is selected from: phenyl, and pyridyl,

wherein phenyl and pyridyl are unsubstituted or substituted with one to three Rb substituents.

In a subclass of this class, Ar1 is selected from: phenyl, and pyridyl, wherein phenyl and pyridyl are unsubstituted or substituted with one to three substituents selected from halogen and cyano.

In another subclass of this class, Ar1 is phenyl, unsubstituted or substituted with one or two Rb substituents.

In still another subclass, Ar1 is phenyl unsubstituted or parasubstituted with an Rb substituent.

In yet another subclass, Ar1 is phenyl substituted in the para-position with halogen or cyano.

In an additional subclass, Ar1 is para-chlorophenyl.

In yet another embodiment of the present invention, Ar2 is selected from:

aryl and heteroaryl, wherein aryl and heteroaryl are unsubstituted or substituted with one to four substituents independently selected from Rb.

In a class of this embodiment, Ar2 is selected from: phenyl, and pyridyl, wherein phenyl and pyridyl are unsubstituted or substituted with one to three Rb substituents.

In a subclass of this class, Ar2 is selected from: phenyl, and pyridyl, wherein phenyl and pyridyl are unsubstituted or substituted with one to three substituents selected from halogen and cyano.

In another subclass of this class, Ar2 is phenyl, unsubstituted or substituted with one or two Rb substituents.

In still another subclass, Ar2 is phenyl unsubstituted or metasubstituted with an Rb substituent.

In yet another subclass, Ar2 is phenyl substituted in the meta-position with halogen or cyano. In an additional subclass, Ar2 is meta-chlorophenyl.

In an additional subclass, Ar2 is selected from: m-chlorophenyl, m-bromophenyl, and m-cyanophenyl.

In a class of the present invention, each Ra is independently selected from: —ORd, halogen, cyano, and CO2Rd.

In a subclass of this class, each Ra is independently selected from: —ORd, —Br, —Cl, —CN, and —CO2C(CH3)3.

In one embodiment of the present invention, each Rc is independently selected from:

(1) hydrogen, and

(2) C1-4alkyl, and

each Rd is independently selected from:

(1) hydrogen,

(2) C1-4alkyl,

(3) C2-6 alkenyl,

(4) cycloalkyl,

(5) cycloalkyl-C1-4alkyl,

(6) cycloheteroalkyl,

(7) cycloheteroalkyl-C1-4alkyl,

(8) phenyl,

(9) heteroaryl,

(10) phenyl-C1-4alkyl, and

(11) heteroaryl-C1-4alkyl, or

Rc and Rd together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—Rg, each Rc and Rd may be unsubstituted or substituted with one to three substituents selected from Rh.

In one class of this embodiment, each Rc is independently selected from: hydrogen, and C1-4alkyl, and

each Rd is independently selected from:

(1) hydrogen,

(2) C1-5alkyl,

(3) —CH2CH═CH2,

(4) cyclohexyl,

(5) cyclopentyl,

(6) cyclopropyl,

(7) cyclobutylmethyl,

(8) cyclopentylmethyl,

(9) cyclohexylmethyl,

(10) pyrrolidinyl,

(11) phenyl,

(12) thiazolyl,

(13) pyridyl,

(14) pyrimidyl,

(15) benzothiazolyl,

(16) benzoxazolyl,

(17) triazolyl,

(18) benzyl, and

(19) pyridyl-methyl-, or

Rc and Rd together with the atom(s) to which they are attached form a piperidinyl ring, each Rc and Rd may be unsubstituted or substituted with one to three substituents selected from Rh.

In a subclass of this class, each Rc is selected from:

(1) hydrogen, and

(2) C1-4alkyl, and

each Rd is independently selected from:

(1) hydrogen,

(2) phenyl,

(3) pyridyl, and

(4) pyrimidyl,

wherein phenyl, pyridyl and pyrimidyl are unsubstituted or substituted with one or two Rh substituents.

In one embodiment of the present invention, each Rg is independently selected from: hydrogen, C1-4alkyl, —C(O)C1-14alkyl, —C(O)ORd, —C(O)NRcRd, —S(O)mRd, and —S(O)mNRcRd.

In one class of this embodiment, each Rg is selected from: hydrogen, C1-4alkyl, and —C(O)C1-4alkyl.

In another class of this embodiment, each Rg is hydrogen, methyl or methylcarbonyl.

In yet another class of this embodiment, each Rh is independently selected from: halogen, methyl, methoxy, —S(O)m—CH3, —CN, —CF3, —CHF2, and —OCF3.

In a subclass of this class, each Rh is selected from: —Cl, —F, —CH3, —CF3, and —CHF2.

In one embodiment of the present invention m is one or two.

In a class of this embodiment, m is two. In another class, m is one.

In another embodiment of the present invention is directed to compounds of structural formula II:

“Alkyl”, as well as other groups having the prefix “alk”, such as alkoxy, alkanoyl, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.

“Alkenyl” means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.

“Alkynyl” means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.

“Cycloalkyl” means mono- or bicyclic or bridged saturated carbocyclic rings, each having from 3 to 10 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooxtyl, tetrahydronaphthyl, decahydronaphthyl, and the like.

“Aryl” means mono- or bicyclic aromatic rings containing only carbon atoms. Examples of aryl include phenyl, naphthyl, and the like.

“Heteroaryl” means a mono- or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, with each ring containing 5 to 6 atoms. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, oxazolidinyl, and the like. The heteroaryl ring may be substituted on one or more carbon atoms. In one embodiment of the present invention, heteroaryl is pyridyl, pyrimidyl, imidazolyl, and thienyl. In one class of this embodiment heteroaryl is pyridyl.

“Cycloheteroalkyl” means mono- or bicyclic or bridged saturated rings containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen. Examples of “cycloheteroalkyl” include pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyranyl, tetrahydrofuranyl, morpholinyl, dioxanyl, oxanyl, azetidinyl, perhydroazepinyl, tetrahydrofuranyl, 1-thia-4-aza-cyclohexane (thiomorpholinyl), hexahydrothienopyridinyl, thienopyridinyl, azacycloheptyl, and the like. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones attached through the nitrogen or N-substituted-(1H, 3H)-pyrimidine-2,4-diones (N-substituted uracils). The cycloheteroalkyl ring may be substituted on the ring carbons and/or the ring nitrogens.

“Halogen” includes fluorine, chlorine, bromine and iodine.

When any variable (e.g., R1, Rd, etc.) occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. For example, a C1-5 alkylcarbonylamino C1-6 alkyl substituent is equivalent to:

In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e., R1, R2, etc., are to be chosen in conformity with well-known principles of chemical structure connectivity and stability.

The term “substituted” shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of Formula I.

Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

Tautomers are defined as compounds that undergo rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.

Compounds of the Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example MeOH or ethyl acetate or a mixture thereof. The pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active amine as a resolving agent or on a chiral HPLC column.

Alternatively, any enantiomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.

It is generally preferable to administer compounds of the present invention as enantiomerically pure formulations. Racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. These include chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.

It will be understood that, as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.

Compounds of the present invention are modulators of the CB1 receptor. In particular, the compounds of structural formula I are antagonists or inverse agonists of the CB1 receptor.

An “agonist” is a compound (hormone, neurotransmitter or synthetic compound) which binds to a receptor and mimics the effects of the endogenous regulatory compound, such as contraction, relaxation, secretion, change in enzyme activity, etc. An “antagonist” is a compound, devoid of intrinsic regulatory activity, which produces effects by interfering with the binding of the endogenous agonist or inhibiting the action of an agonist. An “inverse agonist” is a compound which acts on a receptor but produces the opposite effect produced by the agonist of the particular receptor.

Compounds of this invention are modulators of the CB1 receptor and as such are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, such as for example, to opiates, alcohol, marijuana, and nicotine. The compounds are also useful for the treatment of obesity or eating disorders associated with excessive food intake and complications associated therewith, including left ventricular hypertrophy. The compounds are also useful for the treatment of constipation and chronic intestinal pseudo-obstruction. The compounds are also useful for the treatment of cirrhosis of the liver. The compounds are also useful for the treatment of asthma.

The terms “administration of” and or “administering a” compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.

The administration of the compound of structural formula I in order to practice the present methods of therapy is carried out by administering an effective amount of the compound of structural formula I to the patient in need of such treatment or prophylaxis. The need for a prophylactic administration according to the methods of the present invention is determined via the use of well known risk factors. The effective amount of an individual compound is determined, in the final analysis, by the physician in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions from which the patient suffers, the chosen route of administration other drugs and treatments which the patient may concomitantly require, and other factors in the physician's judgment.

The magnitude of prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, such as, for example, from 0.01 mg to about 50 mg per kg, and further from 0.1 to 10 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.

For use where a composition for intravenous administration is employed, a suitable dosage range is from about 0.001 mg to about 100 mg (such as for example from 0.01 mg to about 50 mg, further from 0.1 mg to 10 mg) of a compound of Formula I per kg of body weight per day.

In the case where an oral composition is employed, a suitable dosage range is, e.g. from about 0.01 mg to about 1000 mg of a compound of Formula I per day, preferably from about 0.1 mg to about 10 mg per day. For oral administration, the compositions are optionally provided in the form of tablets containing from 0.01 to 1,000 mg, such as for example 0.01, 0.05, 0.1, 0.5, 1, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 100, 250, 500, 750 or 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.

Another aspect of the present invention provides pharmaceutical compositions which comprises a compound of Formula I and a pharmaceutically acceptable carrier. The term “composition”, as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of Formula I, additional active ingredient(s), and pharmaceutically acceptable excipients.

Any suitable route of administration may be employed for providing a mammal, especially a human or companion animal such as a dog or cat, with an effective dosage of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.

The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (aerosol inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.

For administration by inhalation, the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulizers. The compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device. The preferred delivery systems for inhalation are metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of Formula I in suitable propellants, such as fluorocarbons or hydrocarbons and dry powder inhalation (DPI) aerosol, which may be formulated as a dry powder of a compound of Formula I with or without additional excipients.

Suitable topical formulations of a compound of formula I include transdermal devices, aerosols, creams, solutions, ointments, gels, lotions, dusting powders, and the like. The topical pharmaceutical compositions containing the compounds of the present invention ordinarily include about 0.005% to 5% by weight of the active compound in admixture with a pharmaceutically acceptable vehicle. Transdermal skin patches useful for administering the compounds of the present invention include those well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course be continuous rather than intermittent throughout the dosage regimen.

In practical use, the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compounds of Formula I may also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719.

Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules (including timed release and sustained release formulations), pills, cachets, powders, granules or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion, including elixirs, tinctures, solutions, suspensions, syrups and emulsions. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound of the invention moistened with an inert liquid diluent. Desirably, each tablet cachet or capsule contains from about 0.01 to 1,000 mg, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 3, 5, 6, 10, 15, 25, 30, 40, 50, 75, 100, 125, 150, 175, 180, 200, 225, 250, 500, 750 and 1,000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.

Additional suitable means of administration of the compounds of the present invention include injection, intravenous bolus or infusion, intraperitoneal, subcutaneous, intramuscular and topical, with or without occlusion.

Exemplifying the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. Also exemplifying the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. An illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.

The dose may be administered in a single daily dose or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, based on the properties of the individual compound selected for administration, the dose may be administered less frequently, e.g., weekly, twice weekly, monthly, etc. The unit dosage will, of course, be correspondingly larger for the less frequent administration.

When administered via intranasal routes, transdermal routes, by rectal or vaginal suppositories, or through a continual intravenous solution, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

The following are examples of representative pharmaceutical dosage forms for the compounds of Formula I:

Injectable Suspension

mg/

(I.M.)

mg/mL

Tablet

tablet

Compound of Formula I

10

Compound of Formula I

25

Methylcellulose

5.0

Microcrystalline Cellulose

415

Tween 80

0.5

Povidone

14.0

Benzyl alcohol

9.0

Pregelatinized Starch

43.5

Benzalkonium chloride

1.0

Magnesium Stearate

2.5

Water for injection to a total

500

volume of 1 mL

mg/

Per

Capsule

capsule

Aerosol

canister

Compound of

25

Compound of Formula I

24

mg

Formula I

Lecithin, NF Liq. Conc.

1.2

mg

Lactose Powder

573.5

Trichlorofluoromethane, NF

4.025

g

Magnesium Stearate

1.5

Dichlorodifluoromethane, NF

12.15

g

600

Compounds of Formula I may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula I are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I. When a compound of Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of Formula I is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula I. Examples of other active ingredients that may be combined with a compound of Formula I include, but are not limited to: antipsychotic agents, cognition enhancing agents, anti-migraine agents, anti-asthmatic agents, antiinflammatory agents, anxiolytics, anti-Parkinson's agents, anti-epileptics, anorectic agents, serotonin reuptake inhibitors, other anti-obesity agents, as well as antidiabetic agents, lipid lowering agents, and antihypertensive agents which may be administered separately or in the same pharmaceutical compositions.

The present invention also provides a method for the treatment or prevention of a CB1 receptor modulator mediated disease, which method comprises administration to a patient in need of such treatment or at risk of developing a CB1 receptor modulator mediated disease of an amount of a CB1 receptor modulator and an amount of one or more active ingredients, such that together they give effective relief.

In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a CB1 receptor modulator and one or more active ingredients, together with at least one pharmaceutically acceptable carrier or excipient.

Thus, according to a further aspect of the present invention there is provided the use of a CB1 receptor modulator and one or more active ingredients for the manufacture of a medicament for the treatment or prevention of a CB1 receptor modulator mediated disease. In a further or alternative aspect of the present invention, there is therefore provided a product comprising a CB1 receptor modulator and one or more active ingredients as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of CB1 receptor modulator mediated disease. Such a combined preparation may be, for example, in the form of a twin pack.

It will be appreciated that for the treatment or prevention of eating disorders, including obesity, bulimia nervosa and compulsive eating disorders, a compound of the present invention may be used in conjunction with other anorectic agents.

The present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an anorectic agent, such that together they give effective relief.

One non-limiting class of anorectic agents includes the halogenated amphetamine derivatives, such as for example, chlorphentermine, cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine; and pharmaceutically acceptable salts thereof.

One embodiment includes the combination of a compound in accordance with the invention admixed with halogenated amphetamine derivatives selected from fenfluramine, dexfenfluramine, and pharmaceutically acceptable salts thereof.

The present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of another agent useful in treating obesity and obesity-related conditions, such that together they give effective relief.

Suitable anti-obesity agents of use in combination with a compound of the present invention, include, but are not limited to:

Specific DP-IV inhibitors of use in combination with a compound of the present invention are selected from:

and pharmaceutically acceptable salts thereof. In particular, the compound of formula I is favorably combined with 7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine.

“Obesity” is a condition in which there is an excess of body fat. The operational definition of obesity is based on the Body Mass Index (BMI), which is calculated as body weight per height in meters squared (kg/m2). “Obesity” refers to a condition whereby an otherwise healthy subject has a Body Mass Index (BMI) greater than or equal to 30 kg/m2, or a condition whereby a subject with at least one co-morbidity has a BMI greater than or equal to 27 kg/m2. An “obese subject” is an otherwise healthy subject with a Body Mass Index (BMI) greater than or equal to 30 kg/m2 or a subject with at least one co-morbidity with a BMI greater than or equal to 27 kg/m2. A “subject at risk for obesity” is an otherwise healthy subject with a BMI of 25 kg/m2 to less than 30 kg/m2 or a subject with at least one co-morbidity with a BMI of 25 kg/m2 to less than 27 kg/m2.

The increased risks associated with obesity occur at a lower Body Mass Index (BMI) in Asians. In Asian countries, including Japan, “obesity” refers to a condition whereby a subject with at least one obesity-induced or obesity-related co-morbidity that requires weight reduction or that would be improved by weight reduction, has a BMI greater than or equal to 25 kg/m2. In Asian countries, including Japan, an “obese subject” refers to a subject with at least one obesity-induced or obesity-related co-morbidity that requires weight reduction or that would be improved by weight reduction, with a BMI greater than or equal to 25 kg/m2. In Asian countries, a “subject at risk of obesity” is a subject with a BMI of greater than 23 kg/m2 to less than 25 kg/m2.

As used herein, the term “obesity” is meant to encompass all of the above definitions of obesity.

“Treatment” (of obesity and obesity-related disorders) refers to the administration of the compounds of the present invention to reduce or maintain the body weight of an obese subject. One outcome of treatment may be reducing the body weight of an obese subject relative to that subject's body weight immediately before the administration of the compounds of the present invention. Another outcome of treatment may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy. Another outcome of treatment may be decreasing the occurrence of and/or the severity of obesity-related diseases. The treatment may suitably result in a reduction in food or calorie intake by the subject, including a reduction in total food intake, or a reduction of intake of specific components of the diet such as carbohydrates or fats; and/or the inhibition of nutrient absorption; and/or the inhibition of the reduction of metabolic rate; and in weight reduction in patients in need thereof. The treatment may also result in an alteration of metabolic rate, such as an increase in metabolic rate, rather than or in addition to an inhibition of the reduction of metabolic rate; and/or in minimization of the metabolic resistance that normally results from weight loss.

“Prevention” (of obesity and obesity-related disorders) refers to the administration of the compounds of the present invention to reduce or maintain the body weight of a subject at risk of obesity. One outcome of prevention may be reducing the body weight of a subject at risk of obesity relative to that subject's body weight immediately before the administration of the compounds of the present invention. Another outcome of prevention may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy. Another outcome of prevention may be preventing obesity from occurring if the treatment is administered prior to the onset of obesity in a subject at risk of obesity. Another outcome of prevention may be decreasing the occurrence and/or severity of obesity-related disorders if the treatment is administered prior to the onset of obesity in a subject at risk of obesity. Moreover, if treatment is commenced in already obese subjects, such treatment may prevent the occurrence, progression or severity of obesity-related disorders, such as, but not limited to, arteriosclerosis, Type II diabetes, polycystic ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.

The term “diabetes,” as used herein, includes both insulin-dependent diabetes mellitus (i.e., IDDM, also known as type I diabetes) and non-insulin-dependent diabetes mellitus (i.e., NIDDM, also known as Type II diabetes. Type I diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone which regulates glucose utilization. Type II diabetes, or insulin-independent diabetes (i.e., non-insulin-dependent diabetes mellitus), often occurs in the face of normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most of the Type II diabetics are also obese. The compounds of the present invention are useful for treating both Type I and Type II diabetes. The compounds are especially effective for treating Type II diabetes. The compounds of the present invention are also useful for treating and/or preventing gestational diabetes mellitus.

It will be appreciated that for the treatment or prevention of migraine, a compound of the present invention may be used in conjunction with other anti-migraine agents, such as ergotamines or 5-HT1 agonists, especially sumatriptan, naratriptan, zolmatriptan or rizatriptan.

It will be appreciated that for the treatment of depression or anxiety, a compound of the present invention may be used in conjunction with other anti-depressant or anti-anxiety agents.

As used herein, the term “substance abuse disorders” includes substance dependence or abuse with or without physiological dependence. The substances associated with these disorders are: alcohol, amphetamines (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, marijuana, nicotine, opioids, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics or benzodiazepines, and other (or unknown) substances and combinations of all of the above.

The term “substance abuse disorders” includes drug withdrawal disorders such as alcohol withdrawal with or without perceptual disturbances; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without perceptual disturbances; sedative, hypnotic or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances. It will be appreciated that reference to treatment of nicotine withdrawal includes the treatment of symptoms associated with smoking cessation.

Other “substance abuse disorders” include substance-induced anxiety disorder with onset during withdrawal; substance-induced mood disorder with onset during withdrawal; and substance-induced sleep disorder with onset during withdrawal.

In particular, compounds of structural formula I are useful for aiding in stopping consumption of tobacco and are useful in treating nicotine dependencies and nicotine withdrawal. The compounds of formula I produce in consumers of nicotine, such as tobacco smokers, a total or partial abstinence from smoking. Further, withdrawal symptoms are lessened and the weight gain that generally accompanies quitting tobacco consumption is reduced or nonexistent. For smoking cessation, the compound of form I may be used in combination with a nicotine agonist or a partial nicotine agonist such as varenicline, or a monoamine oxidase inhibitor (MAOI), or another active ingredient demonstrating efficacy in aiding cessation of tobacco consumption; for example, an antidepressant such as bupropion, doxepine, ornortriptyline; or an anxiolytic such as buspirone or clonidine.

It will be appreciated that a combination of a conventional antipsychotic drug with a CB1 receptor modulator may provide an enhanced effect in the treatment of mania. Such a combination would be expected to provide for a rapid onset of action to treat a manic episode thereby enabling prescription on an “as needed basis”. Furthermore, such a combination may enable a lower dose of the antispychotic agent to be used without compromising the efficacy of the antipsychotic agent, thereby minimizing the risk of adverse side-effects. A yet further advantage of such a combination is that, due to the action of the CB1 receptor modulator, adverse side-effects caused by the antipsychotic agent such as acute dystonias, dyskinesias, akathesia and tremor may be reduced or prevented.

Thus, according to a further aspect of the present invention there is provided the use of a CB1 receptor modulator and an antipsychotic agent for the manufacture of a medicament for the treatment or prevention of mania.

The present invention also provides a method for the treatment or prevention of mania, which method comprises administration to a patient in need of such treatment or at risk of developing mania of an amount of a CB1 receptor modulator and an amount of an antipsychotic agent, such that together they give effective relief.

In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a CB1 receptor modulator and an antipsychotic agent, together with at least one pharmaceutically acceptable carrier or excipient.

It will be appreciated that the CB1 receptor modulator and the antipsychotic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of mania. Such combined preparations may be, for example, in the form of a twin pack.

In a further or alternative aspect of the present invention, there is therefore provided a product comprising a CB1 receptor modulator and an antipsychotic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of mania.

The term “combination” also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. Therefore, by way of example, the antipsychotic agent may be administered as a tablet and then, within a reasonable period of time, the CB1 receptor modulator may be administered either as an oral dosage form such as a tablet or a fast-dissolving oral dosage form. By a “fast-dissolving oral formulation” is meant, an oral delivery form which when placed on the tongue of a patient, dissolves within about 10 seconds.

Included within the scope of the present invention is the use of CB1 receptor modulators in combination with an antipsychotic agent in the treatment or prevention of hypomania.

It will be appreciated that a combination of a conventional antipsychotic drug with a CB1 receptor modulator may provide an enhanced effect in the treatment of schizophrenic disorders. Such a combination would be expected to provide for a rapid onset of action to treat schizophrenic symptoms thereby enabling prescription on an “as needed basis”. Furthermore, such a combination may enable a lower dose of the CNS agent to be used without compromising the efficacy of the antipsychotic agent, thereby minimizing the risk of adverse side-effects. A yet further advantage of such a combination is that, due to the action of the CB1 receptor modulator, adverse side-effects caused by the antipsychotic agent such as acute dystonias, dyskinesias, akathesia and tremor may be reduced or prevented.

Suitable antipsychotic agents of use in combination with a CB1 receptor modulator include the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of antipsychotic agent. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. Suitable examples of dibenzazepines include clozapine and olanzapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone. Other antipsychotic agents include loxapine, sulpiride and risperidone. It will be appreciated that the antipsychotic agents when used in combination with a CB1 receptor modulator may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, olanzapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form.

Other classes of antipsychotic agent of use in combination with a CB1 receptor modulator include dopamine receptor antagonists, especially D2, D3 and D4 dopamine receptor antagonists, and muscarinic ml receptor agonists. An example of a D3 dopamine receptor antagonist is the compound PNU-99194A. An example of a D4 dopamine receptor antagonist is PNU-101387. An example of a muscarinic ml receptor agonist is xanomeline.

Another class of antipsychotic agent of use in combination with a CB1 receptor modulator is the 5-HT2A receptor antagonists, examples of which include MDL100907 and fananserin. Also of use in combination with a CB1 receptor modulator are the serotonin dopamine antagonists (SDAs) which are believed to combine 5-HT2A and dopamine receptor antagonist activity, examples of which include olanzapine and ziperasidone.

Still further, NK-1 receptor antagonists may be favorably employed with the CB1 receptor modulators of the present invention. NK-1 receptor antagonists for use in the present invention are selected from the classes of compounds described previously.

It will be appreciated that a combination of a conventional anti-asthmatic drug with a CB1 receptor modulator may provide an enhanced effect in the treatment of asthma, and may be used for the treatment or prevention of asthma, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an anti-asthmatic agent, such that together they give effective relief. Thus, according to a further aspect of the present invention there is provided the use of a CB1 receptor modulator and an anti-asthmatic agent for the manufacture of a medicament for the treatment or prevention of asthma.

It will be appreciated that a combination of a conventional anti-constipation drug with a CB1 receptor modulator may provide an enhanced effect in the treatment of constipation, or chronic intestinal pseudo-obstruction, and for use for the manufacture of a medicament for the treatment or prevention of constipation or chronic intestinal pseudo obstruction.

The present invention also provides a method for the treatment or prevention of constipation, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an anti-constipation agent, such that together they give effective relief.

Suitable anti-constipation agents of use in combination with a compound of the present invention include, but are not limited to, osmotic agents, laxatives and detergent laxatives (or wetting agents), bulking agents, and stimulants; and pharmaceutically acceptable salts thereof. A class of osmotic agents can include, but is not limited to, sorbitol, lactulose, polyethylene glycol, magnesium, phosphate, sulfate, and pharmaceutically acceptable salts thereof. A class of laxatives and detergent laxatives, include, but are not limited to, magnesium, docusate sodium, and pharmaceutically acceptable salts thereof. A class of bulking agents include, but are not limited to, psyllium, methylcellulose, calcium polycarbophil, and pharmaceutically acceptable salts thereof. A class of stimulants include, but are not limited to, anthroquinones, and phenolphthalein, and pharmaceutically acceptable salts thereof.

It will be appreciated that a combination of a conventional anti-cirrhosis drug with a CB1 receptor modulator may provide an enhanced effect in the treatment of cirrhosis of the liver, and for use for the manufacture of a medicament for the treatment or prevention of cirrhosis of the liver.

The present invention also provides a method for the treatment or prevention of cirrhosis of the liver, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an anti-cirrhosis agent, such that together they give effective relief.

Suitable anti-cirrhosis agents of use in combination with a compound of the present invention include, but are not limited to, corticosteroids, penicillamine, colchicine, interferon-γ, 2-oxoglutarate analogs, prostaglandin analogs, and other anti-inflammatory drugs and antimetabolites such as azathioprine, methotrexate, leflunamide, indomethacin, naproxen, and 6-mercaptopurine; and pharmaceutically acceptable salts thereof.

The method of treatment of this invention comprises a method of modulating the CB1 receptor and treating CB1 receptor mediated diseases by administering to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of this invention that selectively antagonizes the CB1 receptor in preference to the other CB or G-protein coupled receptors.

The term “therapeutically effective amount” means the amount the compound of structural formula I that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disorder being treated. The novel methods of treatment of this invention are for disorders known to those skilled in the art. The term “mammal” includes humans and companion animals such as dogs and cats.

The weight ratio of the compound of the Formula I to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the Formula I is combined with a β-3 agonist the weight ratio of the compound of the Formula I to the β-3 agonist will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the Formula I and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

The compounds of this invention may be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature or exemplified in the experimental procedures. The illustrative schemes below, therefore, are not limited by the compounds listed or by any particular substitutents employed for illustrative purposes. Substituent numbering as shown in the schemes does not necessarily correlate to that used in the claims and often, for clarity, a single substituent is shown attached to the compound in place of multiple substituents which are allowed under the definitions of Formula I defined previously.

In order to illustrate the invention, the following schemes and examples are included. These examples do not limit the invention. They are only meant to suggest a method of reducing the invention to practice. Those skilled in the art may find other methods of practicing the invention which are readily apparent to them. However, those methods are also deemed to be within the scope of this invention.

In Scheme 1, an appropriately substituted hydrazine A is reacted with a carboxylic acid B under standard amide bond forming conditions to afford the carboxylic acid hydrazide C. In order to illustrate the invention, the following examples are included. These examples do not limit the invention. They are only meant to suggest a method of reducing the invention to practice. Those skilled in the art may find other methods of practicing the invention which are readily apparent to them. However, those methods are also deemed to be within the scope of this invention.

General Procedures. The LC/MS analyses were preformed using a MICROMASS ZMD mass spectrometer coupled to an AGILENT 1100 Series HPLC utilizing a YMC ODS-A 4.6×50 mm column eluting at 2.5 mL/min with a solvent gradient of 10 to 95% B over 4.5 min, followed by 0.5 min at 95% B: solvent A=0.06% TFA in water; solvent B=0.05% TFA in acetonitrile. 1H-NMR spectra were obtained on a 500 MHz VARIAN Spectrometer in CDCl3 or CD3OD as indicated and chemical shifts are reported as δ using the solvent peak as reference and coupling constants are reported in hertz (Hz).

To a solution of 3-chlorobenzylaldehyde (4.3 mL, 38 mmol) in 100 mL of benzene was added 5 g of 4 Å molecular sieves and methylamine (95 mL of 2M solution in THF, 190 mmol). After the reaction mixture was stirred at rt overnight, the molecular sieves was removed by filtration, and concentration of the filtrate afforded the crude imine, which was dissolved in 100 mL of anhydrous THF and was added 4-chlorobenzylmagnesium chloride (0.25M in Et2O, 168 mL, 42 mmol) via canula at −10° C. The cooling bath was removed and the reaction was stirred at rt for 1 h. The reaction was quenched with aqueous NH4Cl, made basic with 2N NaOH, and extracted with EtOAc. The organic extracts were dried over MgSO4, filtered, and concentrated in vacuum to afford the title compound which was used in the next step without further purification. 1H NMR (500 MHz, CD3OD): δ 7.32 (s, 1H), 7.24-7.21 (m, 3H), 7.17 (d, 2H), 6.97 (d, 2H), 3.70 (dd, 1H), 3.05 (dd, 1H), 2.82 (dd, 1H), 2.19 (s, 3H). LC-MS: m/e 280 (M+H)+ (2.5 min).

To a solution of 3-chlorobenzylaldehyde (42.3 mL, 20 mmol) in 50 mL of benzene was added 5 g of 4 Å molecular sieves and ethylamine (50 mL of 2 M solution in THF, 100 mmol). After the reaction mixture was stirred at rt overnight, the molecular sieves were removed by filtration, and the filtrate was concentrated to give the crude imine, which was dissolved in 60 mL of anhydrous THF. 4-chlorobenzylmagnesium chloride (0.25M in Et2O, 120 mL, 30 mmol) was added at −10° C. The cooling bath was removed and the reaction was stirred at rt for 1 h. The reaction was quenched with aqueous NH4Cl, made basic with 2N NaOH, and extracted with EtOAc. The organic extracts were dried over MgSO4, filtered, and concentrated in vacuum to afford the title compound which was used in the next step without further purification. 1H NMR (500 MHz, CD3OD): δ 7.33 (s, 1H), 7.24-7.21 (m, 3H), 7.18 (d, 2H), 6.98 (d, 2H), 3.81 (dd, 1H), 3.06 (dd, 1H), 2.81 (dd, 1H), 2.42 (m, 2H), 1.03 (t, 3H).

To a solution of 3-chlorobenzylaldehyde (3.4 mL, 30 mmol) in 100 mL of benzene was added 8 g of 4 Å molecular sieves and allylamine (11.3 mL, 150 mmol). After stirring at rt overnight, the molecular sieves was removed by filtration, and the filtrate was concentrated to give the crude imine, which was dissolved in 100 mL of anhydrous THF and was added 4-chlorobenzylmagnesium chloride (0.25M in Et2O, 180 mL, 45 mmol) at −10° C. The cooling bath was removed and the reaction was stirred at rt for 1 h. The reaction was quenched with aqueous NH4Cl, made basic with 2N NaOH, and extracted with EtOAc. The organic extracts were dried over MgSO4, filtered, and concentrated in vacuum to afford the title compound which was used in the next step without further purification. 1H NMR (500 MHz, CD3OD): δ 7.33 (s, 1H), 7.21 (m, 3H), 7.18 (d, 2H), 6.98 (d, 2H), 5.80 (m, 1H), 5.04 (s, 1H), 5.02 (d, 1H), 3.82 (dd, 1H), 3.03 (dd, 1H), 2.98 (dd, 1H), 2.82 (dd, 1H).

To a solution of 2-fluorophenol (2.0 g, 18 mmol) and 1,1,1-trichloro-2-methyl-2-propanol (7.9 g, 45 mmol) in acetone (100 mL) was added sodium hydroxide (7.1 g, 0.18 mol), and an ice-water bath was periodically applied to maintain a gentle reflux. After the reflux subsided, the reaction was stirred for one additional hour. The volatile materials were removed on a rotary evaporator, and the residue partitioned between ether (100 mL), hexane (100 mL) and water (200 mL). The aqueous layer was separated and acidified with concentrated hydrochloric acid (pH=2), and extracted with ether (3×100 mL). The combined extracts were dried over anhydrous MgSO4, filtered, and concentrated to dryness to give the title compound, which was used without further purification. 1H NMR (500 MHz, CD3OD): δ 7.15-7.05 (m, 4H), 1.56 (s, 6H). LC-MS: m/e 199 (M+1)+ (2.3 min).

The acids of Reference Examples 6 and 7 were prepared following the procedures described for Reference Example 5 substituting 2-fluorophenol with appropriately substituted phenols.

To a solution of 2-chloro-5-iodopyridine (18 g, 75 mmol) in ether (100 mL) and tetrahydrofuran (100 mL) at −78° C. was added tert-butyllithium (1.7 M in pentane, 60 mL, 100 mmol). After stirring at −78° C. for 30 min, DMF (11 mL, 150 mmol) was added, and the reaction was allowed to warm up to 0° C. over 30 min, and was poured into a stirred mixture of ice (200 g), concentrated hydrochloric acid (20 mL) and ether (200 mL). The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel eluting with 0 to 10% ether in hexane/dichloromethane (1:1) to give the title compound. 1H NMR (500 MHz, CD3OD): 10.18 (s, 1H), 8.90 (s, 1H), 8.17 (d, 1H), 7.55 (d, 1H).

Step B 4-Chloro-3-difluoromethylpyridine

To a solution of 4-chloro-3-pyridinecarboxaldehyde (3.7 g, 26 mmol) in 15 mL of dichloromethane at −78° was added (dimethylamino)sulfur trifluoride (15 mL, 0.15 mol), and the reaction was allowed to warm up to room temperature overnight. The reaction was quenched by carefully transferring into a mixture of ice (100 g) and sodium sulfite (10 g). The product was extracted with ether (100 mL×2), and the combined extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel eluting with 0 to 10% ether in hexane to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.59 (s, 1H), 7.84 (d, 1H), 7.48 (d, 1H), 6.74 (t, 1H).

Step C 2-Methyl-2-(5-difluoromethyl-2-pyridyloxy)propionic Acid

The title compound (1.6 g) was prepared from 4-chloro-3-difluoromethylpyridine (3.0 g) following the procedure described for Reference Example 15 with the following modifications. The ester intermediate was purified by flash column chromatography on silica gel eluting with 0 to 10% ether in hexane. The hydrolysis of the ester to the title compound was effected with lithium hydroxide in methanol/tetrahydrofuran/water. 1H NMR (500 MHz, CD3OD): δ 8.22 (d, 1H), 7.82 (dd, 1H), 6.88 (d, 1H), 6.77 (t, 1H), 1.64 (s, 6H).

To a solution of ethyl cyclobutanecarboxylate (1.0 g, 7.8 mmol) and methyl iodide (2.4 mL, 39 mmol) in 20 mL of anhydrous tetrahydrofuran at −78° C. was added potassium hexamethyldisilazide (0.5 M in toluene, 23 mL, 12 mmol), and the reaction was allowed to warm to room temperature overnight. After quenching with saturated ammonium chloride (10 mL), the resulting mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness to give the title compound, which was used without further purification. 1H NMR (500 MHz, CD3OD): δ 4.12 (q, 2H), 2.5-1.8 (m, 6H), 1.48 (s, 3H), 1.25 (t, 3H).

Step B 1-Methylcyclobutanecarboxylic Acid

To a solution of ethyl 1-methylcyclobutanecarboxylate (Step A, 1.0 g, 7.0 mmol) in water (10 mL) and dioxane (10 mL) was added lithium hydroxide monohydrate (2 g, 48 mmol), and the mixture was heated at 100° C. for 2 days. After cooling to room temperature, the reaction was quenched with 2 M hydrochloric acid to pH=2, and the resulting mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness to give the title compound, which was used without further purification. 1H NMR (500 MHz, CD3OD): δ 2.5-1.8 (m, 6H), 1.39 (s, 3H).

The title compound was prepared following the same procedure as described for Reference Example 9 substituting methyl iodide with isopropyl iodide at Step A and potassium hydroxide in dimethylsulfoxide and water for lithium hydroxide in dioxane and water. 1H NMR (500 MHz, CD3OD): δ 2.7-1.7 (m, 7H), 0.93 (d, 6H).

Compounds of Examples 2-13 (Table 1) were prepared from hydrazines of Reference Example 2-4 and the appropriate carboxylic acid of Reference Examples or commercial sources following the procedures described in Example 1.

The compounds, found in Examples 1-18 were tested in the above assay and found to have an IC50 value of 2 micromolar or less.

Selective CB1 antagonist/inverse agonist compounds have IC50s 100-fold greater in the CB2 binding assay than in the CB1 assay, and generally have IC50s of greater than one micromolar in the CB2 binding assay.

To determine the antagonist activity of test compound, the reaction mixture also contains 0.5 nM of the agonist CP55940, and the reversal of the CP55940 effect is quantitated. Alternatively, a series of dose response curves for CP55940 is performed with increasing concentration of the test compound in each of the dose response curves.

The functional assay for the CB2 receptor is done similarly with recombinant human CB2 receptor expressed in CHO cells.

CB1 antagonist/inverse agonist compounds of the present invention generally have EC50s of less than 1 micromolar in the CB1 functional assay and selective CB1 antagonist/inverse agonists have generally have EC50s of greater than 1 micromolar in the CB2 functional assay.

Adult rats or mice are used in these studies. After at least 2 days of acclimation to the vivarium conditions (controlled humidity and temperature, lights on for 12 hours out of 24 hours) food is removed from rodent cages. Experimental compounds or their vehicles are administered orally, intraperitoneally, subcutaneously or intravenously before the return of a known amount of food to cage. The optimal interval between dosing and food presentation is based on the half-life of the compound based on when brain concentrations of the compound is the highest. Food remaining is measured at several intervals. Food intake is calculated as grams of food eaten per gram of body weight within each time interval and the appetite-suppressant effect of the compounds are compared to the effect of vehicle. In these experiments many strains of mouse or rat, and several standard rodent chows can be used.

Adult rats or mice are used in these studies. Upon or soon after weaning, rats or mice are made obese due to exclusive access to diets containing fat and sucrose in higher proportions than in the control diet. The rat strains commonly used include the Sprague Dawley bred through Charles River Laboratories. Although several mouse strains may be used, c57B1/6 mice are more prone to obesity and hyperinsulinemia than other strains. Common diets used to induce obesity include: Research Diets D12266B (32% fat) or D12451 (45% fat) and BioServ S3282 (60% fat). The rodents ingest chow until they are significantly heavier and have a higher proportion of body fat than control diet rats, often 9 weeks. The rodents receive injections (1 to 4 per day) or continuous infusions of experimental compounds or their vehicles either orally, intraperitoneally, subcutaneously or intravenously. Food intake and body weights are measured daily or more frequently. Food intake is calculated as grams of food eaten per gram of body weight within each time interval and the appetite-suppressant and weight loss effects of the compounds are compared to the effects of vehicle.